A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity

Cell, Год журнала: 2017, Номер 172(1-2), С. 373 - 386.e10

Опубликована: Дек. 7, 2017

Язык: Английский

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Universal Patterns of Selection in Cancer and Somatic Tissues

Cell, Год журнала: 2017, Номер 171(5), С. 1029 - 1041.e21

Опубликована: Окт. 19, 2017

Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures selection in cancer evolution are lacking. We adapted methods from molecular applied them to 7,664 tumors across 29 types. Unlike species evolution, positive outweighs negative during development. On average, <1 coding base substitution/tumor is lost through with purifying almost absent outside homozygous loss essential genes. This allows exome-wide enumeration all driver mutations, including known carry ∼4 substitutions under ranging <1/tumor thyroid testicular cancers >10/tumor endometrial colorectal cancers. Half occur yet-to-be-discovered With increasing burden, numbers mutations increase, not linearly. systematically catalog genes show that vary extensively what proportion drivers versus passengers.

Язык: Английский

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Somatic mutant clones colonize the human esophagus with age

Science, Год журнала: 2018, Номер 362(6417), С. 911 - 917

Опубликована: Окт. 19, 2018

The mutational burden of aging As people age, they accumulate somatic mutations in healthy cells. About 25% cells normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing normal esophageal epithelium from nine human donors varying age (see the Perspective by Chanock). mutation rate was lower esophagus than skin, but there a strong positive selection clones carrying 14 cancer-associated genes. By middle more half colonized mutant clones. Interestingly, NOTCH1 were common cancer. Science , this issue p. 911 ; see also 893

Язык: Английский

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Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Cell Reports, Год журнала: 2018, Номер 23(1), С. 239 - 254.e6

Опубликована: Апрель 1, 2018

Summary

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 types. Mutations with accompanying loss heterozygosity were observed in over 1/3 genes, including TP53 BRCA1/2. Other prevalent included epigenetic silencing the direct genes EXO5, MGMT, ALKBH3 ∼20% samples. Homologous recombination (HRD) was present at varying frequency many types, most notably ovarian cancer. However, contrast cancer, HRD associated worse outcomes several other cancers. Protein structure-based analyses allowed us predict functional consequences rare, recurrent mutations. A new machine-learning-based classifier developed from gene expression data identify that phenocopy deleterious These frequent human cancers have may determine progression guide therapy.

Язык: Английский

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The evolutionary history of 2,658 cancers

Nature, Год журнала: 2020, Номер 578(7793), С. 122 - 128

Опубликована: Фев. 5, 2020

Cancer develops through a process of somatic evolution

Язык: Английский

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Clonal hematopoiesis in human aging and disease

Science, Год журнала: 2019, Номер 366(6465)

Опубликована: Окт. 31, 2019

As people age, their tissues accumulate an increasing number of somatic mutations. Although most these mutations are little or no functional consequence, a mutation may arise that confers fitness advantage on cell. When this process happens in the hematopoietic system, substantial proportion circulating blood cells derive from single mutated stem This outgrowth, called "clonal hematopoiesis," is highly prevalent elderly population. Here we discuss recent advances our knowledge clonal hematopoiesis, its relationship to malignancies, link nonmalignant diseases aging, and potential impact immune function. Clonal hematopoiesis provides glimpse into selection likely occurs all tissues.

Язык: Английский

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Phagocytosis checkpoints as new targets for cancer immunotherapy

Nature reviews. Cancer, Год журнала: 2019, Номер 19(10), С. 568 - 586

Опубликована: Авг. 28, 2019

Язык: Английский

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Prediction of acute myeloid leukaemia risk in healthy individuals

Nature, Год журнала: 2018, Номер 559(7714), С. 400 - 404

Опубликована: Июль 1, 2018

Язык: Английский

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Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

Journal of Clinical Investigation, Год журнала: 2018, Номер 128(10), С. 4654 - 4668

Опубликована: Сен. 9, 2018

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in treatment of several types cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression responsive therapy, suggesting that other immune cell may also play a role. Here, we employed mouse models cancer investigate effect on NK cells, population innate lymphocytes mediate immunity. We discovered PD-1 and PD-L1 elicited strong response was indispensable for full therapeutic immunotherapy. expressed within transplantable, spontaneous, genetically induced tumor models, resulted reduced responses generation more aggressive tumors vivo. abundant an activated phenotype did not mark exhausted phenotype. These demonstrate importance inhibiting vivo reveal addition

Язык: Английский

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Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer

Cell, Год журнала: 2020, Номер 181(7), С. 1612 - 1625.e13

Опубликована: Июнь 1, 2020

Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection unknown. from human tumors and non-malignant tissue were assessed with single-cell RNA paired cell receptor (TCR) sequencing of 30,604 7 patients. We find the states repertoires CD8+ not distinct compared tissues. In contrast, analysis CD4+ demonstrates several tumor-specific states, including multiple regulatory cells. Surprisingly, we also cytotoxic clonally expanded. These can kill autologous an MHC class II-dependent fashion suppressed by Further, a gene signature predicts clinical response 244 metastatic cancer patients treated anti-PD-L1.

Язык: Английский

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